1. Field of the Invention
The present invention is a method of sensitizing desensitized cancer cells to various chemotherapeutic agents so as to better treat the cancer.
2. Description of the Related Art
It is known that cancer cells become resistant to some chemotherapeutic agents and are even resistant to many different chemotherapeutic agents. This is a significant impediment to cancer chemotherapeutic treatment.
It would be of great benefit to those who have cancers which can be treated with chemotherapeutic agents to have an agent which will sensitize the resistant cancer cells to the chemotherapeutic agents being used to treat the cancer.
Several classes of compounds which sensitize cancer cells to chemotherapeutic agents are known. One group of compounds are calcium channel blockers or related analogues, some of which no longer act as calcium channel blockers. For example, some synthetic isoprenoids Cancer Research 46, 4453 (1986) and pyridine analogs Int. J. Cancer 45,508 (1990), cause multidrug resistance reversal. Reserpine Biochem. Pharmacol. 30, 2191 (1981), quinidine and cyclosporine and related analogs J. Clin. Invest. 77, 1405 (1986) some without the original bioactivities, also sensitize multidrug resistance cells. Phenothiazines such as the calmodulin inhibitors thioridazine, trifluoperazine and chlorpromazine J. Nat. Cancer Inst. 76, 839 (1986) and Cancer Let. 30, 25 1 (1986) sensitize multidrug resistant cells. Analogs of Vinca alkaloids and anthracyclines such as N-acetyldaunorubicin Cancer Res. 40, 1077 (1980) will also sensitize multidrug resistant cells, as will steroids J. Biol. Chem. 264, 782 (1989), and Biochem. Biophys. Res. Commun. 158, 1066 (1989)]. Other agents that sensitize multidrug resistant cells include the antibiotic cefoperazone Cancer Research 49, 6901 (1989), tamoxifen Cancer Res. ,,4, 4392 (1984), vitamin A, Br. J. Cancer 56, 267 (1987) and chloroquine Cancer Lett. 30, 251 (1986).
At least two features seem to be of major importance in determining whether a compound can act as a sensitizer. One is lipophilicity Cancer Res. 50, 3997 (1990) and the other is ability to modulate binding on the P-glycoprotein, Advances In Pharmacol., 21,185 (1990). Several of the previously identified sensitizing compounds appear to act by competing for binding to the P-glycoprotein. The mode of action of others that do not compete for binding is unknown.
The steroidal amines (I) are known, see International Publication No. WO87/01706, published Mar. 26, 1987 based on International Patent Application No. PCT/US86/01797.
The alkyl amines (II) and the bicyclic amines (III) are known, see International Publication No. WO88/08424, published Nov. 3, 1988 based on International Patent Application No. PCTAJS88/01212.
The bicyclic ethers (IV) are known, see for example, U.S. Pat. Nos. 4,206,123, 4,577,021, 4,711,960 and 4,487,774. In addition U.S. Pat. Nos. 4,066,648, 4,179,510 and 4,206,113 also disclose bicyclic ethers (IV).
The tricyclic amines (V) am known see U.S. Pat. No. 4,487,774.
Internation Patent Publication WO87/07895 disclosed compounds of the type set forth in ENUMERATED EMBODIMENT 36.
It has been found that various steroidal and non-steroidal amines also sensitize desensitized cancer cells to the common chemotherapeutic agents. These sensitizing compounds are useful in anti-cancer therapy to sensitize cancer cells to be killed by traditional cytotoxic drugs (chemotherapeutic agent). More particularly, 21-[4-2,6-di-1-pyrrolidinyl)-4-pyrimidinyl-1-piperazinyl]-16.alpha.-methyl pregna-1,4,9(11)-triene-3,20-dione (tirilazad mesylate) sensitizes desensitized cancer cells as well as or better than verapamil, which is a standard sensitizer. Verapamil has the disadvantage of causing cardiac toxicity in humans at doses that are required for in vivo sensitization of cancer cells.